This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. The systemic spread and protean nature of Lyme disease lends to difficult diagnosis and often prolonged illness. Vaccination remains the best means of control. Transmission of the Borrelia burgdorferi (Bb) spirochete is through the bite of an Ixodes sp. tick. Those who have been infected are neither impervious to a subsequent tick bite nor to reinfection, so immunity to tick salivary components and Bb antigens are insufficient for protection. Tick saliva possesses components responsible for modulation of the immune response, which may contribute to meager immunity to subsequent infection. The immune response at the site of tick feeding and infection, specifically which is proffered by the antigen-presenting cells (APCs) in skin, is the subject of this project. Though the skin is the natural route of infection, immunization against Bb has been focused exclusively in the parenteral routes. The central hypotheses are that tick saliva modulates cutaneous responses that impair primary cell-mediated immunity (CMI) and that priming APCs in skin with a Bb immunogen can diminish this inhibition. We have shown that the activation of monocytes in response to Bb is significantly dampened by tick saliva. Yet, the primary response in the skin and subsequent impact on CMI has not been explored. Specific aim (SA)1 will be to define the immunomodulatory effects of tick saliva on the immune response generated in skin against Bb using a murine ex vivo model. SA2 will be to assess, in vivo, the impact of tick saliva on activation and migration of dendritic cells from the skin to the lymph nodes in response to antigen. SA3 will be to utilize an appropriate Bb antigen (DbpA) to prime the immune response in the skin and evaluate both ex vivo and in vivo, the impact on immunity against tick-transmitted Bb. These studies have the potential to impact our understanding and possible prevention of not only Lyme disease, but other vector-borne diseases as well.